recognized as a treatable feature in some patients with adult HD. C.M.V. is a recipient of National Institutes of Health Training Grant 5-732 NS-07222. Presented in part at the 114th Annual Meeting of the American Neurological Association, New Orleans, LA, September 1789.
Continuous Muscle Fiber Activity, Peripheral Neuropathy, and Thymoma A. Garcia-Merino, MD,” A. Cabello, MD,? J. S. Mora, MD,” and H. Liatio. MU”
References 1. Jarvis GA. Huntington’s chorea in childhood. Arch Neurol 1963;9:244-257 2. Novum S, Dannd S, Goldberg MA. Intention myoclonus in Huntington’s disease. Bull LA Neurol Sci 1976;41:82-84 3. Kereshi S, Schlagenhauff RE, Richardson KS. Myoclonic and major seizures in early adult Huntington’s chorea: case-report and electroclinical findings. Clin Electroencephalogr 1980;ll: 44-47 4. Previdi P, Borgonovi R. Myoclonus and Huntington’s chorea: description of a case. Ital J Neurol Sci 1980;3:189-192 5. Berkovic SF, Andermann F, Carpenter L, Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med 1986;315:296-305 6. LeWitt PA, Truong DD, Hashimoto K, ec al. ‘Tweed Ball” mitochondropathy with a unique neurodegenerative disorder. Ann Neurol 1989;26:122 7 . Leibel RL, Shih VE, Goodman SI, et al. Glutaric acidemia: a metabolic disorder causing progressive choreoathetosis. Neurology 1980;30:1163-1168 8. Shibasaki H , Sakai T, Nishimura H, et al. Involuntary movements in chorea-acanthocytosis:a comparison with Huntington’s chorea. Ann Neurol 1982;12:311-314 9. Hallett M. Myoclonus: relation to epilepsy. Epilepsia 1985; 2 6 ( ~ ~ p1):S67-S77 pl 10. Enna SJ, Ferkany JW, Van Woert M, Butler IJ. Measurement of GABA in biological fluids: effect of GABA transaminax inhbitors. In: Chase TN, Wexler NS, Barbeau A, eds. Adv Neurol, vol 23. New York: Raven Press, 1979:741-750 11. Airaksinen EM, Leino E. Decrease of GABA in the cerebrospinal fluid of patients with progressive myoclonus epilepsy and its correlation with the decrease of 5 HIAA and HVA. Acta Neurol Scand 1982;66:666-672 12 Meldrum B, Horton R. Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA 4amino-hex-5-ynoic acid and gamma-vinyl GABA (4-amino-hex5-enoic acid). Psychopharmacology 1978;59:47-50 13 Tarsy D, Pycock CJ, Meldrum BS, Marsden CD. Focal contralateral myoclonus produced by inhibition of GABA action in the caudate nucleus of rats. Brain 1978;101:143-162 14 Van Woerr MH, Rosenbaum D, Chcng E. Biochemistry and therapeutics of posthypoxic myoclonus. In: Fahn S, Marsden CD, Van Woert MH, eds. Adv Neurol, vol 43. New York: Raven Press, 1986:171-182 15 Albin RL, Reiner A, Anderson KD, et al. Striatal and nigral subpopulations in rigid Huntington’s disease: implications for the functional anatomy of chorea and rigidity. Ann Neurol 1990;27 :357- 36 5 16 Garant DS, Gale K. Lesions of the substantid nigra protect against experimentally induced seizures. Brain Res 1783;273: 156- 161 17 Bonhaus DW, Walters JR, McNamara JO. Activation of substantia nigra neurons: role in the propagation of seizures in kindled rats. J Neurosci 1086;6:3024-3030 18 Gusella JF, Wexler NS, Connedy PM, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 1983:306:234-238
Two patients, one of them with myasthenia gravis, presented symptoms of continuous muscle fiber activity syndrome before discovery of a thymoma Peripheral neuropathy was present in both patients, with axonal and demyelinating lesions in sural nerve biopsy. T h e syndrome remained unchanged or worse after thymectomy. Both patients died of associated complications. Garcia-Merino A, Cabello A, Mora JS, Liafio H. Continuous muscle fiber activity, peripheral neuropathy, and thymoma. Ann Neurol 1991;29:215-218
The syndrome of continuous muscle fiber activity at rest (CMFAS) [ 1J associates a wide spectrum of clinical manifestations with spontaneous electromyographic (EMG) discharges. T h e condition is a polymorphous entity described under various names such as neuromyotonia, pseudomyotonia, Isms’ syndrome, and CMFAS {2). W e report here two patients with CMFAS, thymoma, and peripheral neuropathy, an association previously not recognized. T h e purpose of this report is to draw attention to the possible relevance of thymoma in the pathogenesis of the syndrome.
Patient Reports
Patient 1 A 56-year-old, previously healthy woman began to note facial twitching, blurred vision, occasional trismus, and soon after, vague thoracic discomfort. Six months after onset of symptoms, a large lymphoepithelial thymoma was found and resected. A few days after surgery, she developed profuse sweating, widespread muscle twitching, dyspnea, and carpal spasms. Serum calcium and magnesium were normal and intravenous calcium did not modify the spasms, which were only relieved by diazepam. Her condition deteriorated progressively. Her dyspnea became present on minimal effort and she developed laryngeal stridor. Extensor spasms of the
From the *Department of Neurology, Clinica Puerta de Hierro, Universidad Autdnoma de Madrid, and the TDeparment of Neuropathology, Hospital “12 de Octubre,” Madrid, Spain. Received Jul 27, 1989, and in revised form Apr 2, Jul 24, and Aug 27, 1990. Accepted for publication Aug 30, 1990. Address correspondence to Dr Garcia-Merino, Departamento de Neurologia, Clinica Puerta de Hierro, San Martin de Porres, 4, 28035 Madrid, Spain.
Copyright 0 1991 by the American Neurological Association
215
Motor Nerve Conduction Velocity Studies in the 2 Patients
Patient 1 Nerve R. median R. ulnar R. peroneal R. tibial Patient 2 Nerve R. peroneal R. tibial L. tibial
LATN (msec)
AMPL (mV)
CV ( d s e c )
F min (msec)
7.9 (2.5-4.4) 3.3 (2.1-3.3) 9.2 (3.3-6.5) 6.3 (3.0-5.8)
4.1 (5-18) 3.2 (6.6-15) 2.3 (2.5-12) 4.9 (4-19)
36 (49-70) 44 (49-70) 43 (44-57) NR (41-58)
31.7 32.3 51.5 52.1
5.0 (3.3-6.5) 7.3 (3.0-5.8) 7.5 (3.0-5.8)
2.1 (2.5-12) 5.6 (4-19) 5.2 (4-19)
41 (44-57) 35 (41-58) 38 (41-58)
52.2 (40-52) 52.5 (41-53) 51.9 (41-53)
(22-31) (22-32) (40-52) (41-53)
Normal values appear in parentheses.
LATN = distal latency; AMPL
= amplitude; CV = conduction velocity;
F rnin
=
F wave of shortest latency; R
=
right; L
=
left; NR
= no
response.
feet made walking impossible. Three months after surgery, she was bedridden and was transferred to our hospital. On admission, she had dyspnea and tachypnea at rest, hypophonia, laryngeal stridor, hyperhidrosis, and widespread myokymias. Her calf musculature was contracted and stiff, and her feet were fixed in plantar flexion. She had severe masseter contraction. An inflated cuff induced carpal spasms. Muscle strength of upper extremities and proximal muscles of lower extremities was normal. Percussion myotonia was not found, and laryngoscopy was negative. There was generalized areflexia and distal loss of vibration perception. Hemogram, blood chemistry, T, and T,, and calcium magnesium levels were normal. Antinuclear and antistriated muscle antibodies were positive at 11640 and 1/320, respectively. Motor nerve conduction studies showed moderately prolonged distal latencies and slowing of conduction to 10 to 20% below normal values (Table). Sural nerve action potentials (NAPS) were absent. Median nerve repetitive stimulation at 3 Hz was normal. Concentric needle exam of first dorsal interosseus, tibialis anterior, and medial gastrocnemius revealed continuous muscle fiber activity at rest, which was composed of bursts of normal and polyphasic units firing at variable frequencies, neuromyotonic discharges, and occasional triplets and multiplets. Fibrillation potentials, positive sharp waves, fasciculations, or myotonic discharges were not recorded. Inflation of a proximal blood cuff produced immediate cessation of activity, which returned 30 seconds later at a lesser intensity on maintenance of ischemia. Sciatic nerve block at the popliteal fossa reduced moderately the frequency of discharges. ELECTROPHYSIOLOGICALSTUDIES.
PATHOLOGICAL STUDIES. Small atrophic angulated muscle fibers were present on gastrocnemius muscle biopsy, together with type grouping (Fig 1). On surd nerve biopsy, there was a mild to moderate loss of large myelinated fibers (5,890/mmZ),frequent vacuolization and splitting of the myelin sheath's outer lamellae, and paranodal demyelination by electron microscopy (not shown).
Three days after admission, the patient suffered a respiratory arrest during a prolonged episode of
CLINICAL COURSE.
216 Annals of Neurology Vol 29 N o 2 February 1991
Fig I . Patient 1. Skeletal muscle. Atrophic, angulatedlfibersare seen in one fascicle, together with type I grouping. (Adenosine tripbospbatase pH 9.4; original magnijkation,, x 1OO.j
laryngeal stridor. She was intubated and placed on a respirator. One day later, she developed severe abdominal pain and shock. An emergency laparotomy revealed a massive mesenteric thrombosis, and the patient died a few hours later. Autopsy was not authorized.
Patient 2 A 68-year-old man with chronic bronchitis had a 12-year history of myasthenia gravis, which was adequately controlled by low doses of pyridostigmine bromide. Two months before admission, he developed nasal voice, dysphagia, regurgitation, and generalized weakness, accompanied by mild dyspnea, profuse perspiration, somnolence, and lower extremity myokymias. A mediastinal mass was found on radiography, and he was referred to our hospital for surgery. O n admission, besides prior symptoms, he had early fatigue on resistive testing of proximal muscles but no ptosis or diplopia. H e was areflexic and had loss of vibration perception in lower limbs. An edrophonium test relieved moderately his nasal speech and early fatigability. Blood chemistry was normal. Antinuclear and antistriated muscle antibodies were positive
at l/l60 and 11320, respectively. Acetylcholine receptor antibodies were 6 nmol/L. ELECTROPHYSIOLOGICM- STUDIES. He had moderately prolonged motor distal latencies, mild slowing of motor conduction to 10 to 20% below normal values, and absent sural NAPS.Facial nerve repetitive stimulation at 1 Hz produced a 21% decrement of the fifth potential. Needle exam of the left tibialis anterior and medial gastrocnemius muscles revealed spontaneous activity composed of bursts of normal units firing at variable rates, sometimes as high as 40 Hz, neuromyotonic discharges, and electrical myokymia. Sciatic nerve block at the popliteal fossa reduced the activity moderately. PATHOLOGICAL STUDIES. Lateral gastrocnemius muscle biopsy with oxidative enzyme staining showed abundant small, dark, angulated fibers and type grouping. Surd nerve biopsy revealed mild to moderate loss of large myelinated fibers (6,7041mm2) and some vacuolation of myelin sheaths (Fig 2A). On electron microscopy, there was extensive vacuolation and dehiscence of the myelin outer lamellae, and in some axons, high concentration of granular material. Teased fibers showed instances of segmental demyelination and remyelination (Fig 2B). Staining with antihuman IgG peroxidase antibodies did not disclose IgG deposits in nerve.
A large epithelial thymic tumor infiltrating pleura and pericardium was removed at thoracotomy. Bronchopulmonary infections complicated the postoperative course, and the man was never able to breathe without assisted respiration. His muscle twitching did not respond well to 800 mgiday of carbamazepine but worsened with anticholinesterase therapy, as did the sweating. The patient’s circulatory instability impeded adequate plasma exchanges. Steroid therapy from an initial dose of 2 mg/kg/day of rnethylprednisolone to a final dose of 20 mg daily, in 6 weeks, did not produce a significant improvement. The patient died 45 days after surgery. Autopsy was not performed. CLINICAL COURSE.
Discassion It has been suggested that the muscle hyperactivity of CMFAS is due to partial loss of motor innervation, compensated by collateral sprouting of survival axons {2]. CMFAS has been associated with different peripheral neuropathies, but the pathological information is very limited. Axonal damage 131, segmental demyelination [4, 53, or both [b] have been reported. In many patients, the surd nerve was normal or showed minimal changes. In others, an increased collateral ramification of terminal motor axons at the preterminal level has been detected [2, 7, 81, expressing denervation without disease specificity. Recently, extensive terminal arborizations in the endplates have been described 191. In our patients, damage to the myelin sheaths seemed independent of the axonal lesion, but the electrophysiologiral results suggested an axonal type of neuropathy . There are a few reports of peripheral nerve disease
Fig 2. Patient 2. Surval nerve. (A) Loss of myelinatedfibers and Some completely demyelinated axons. (Semithin section, toluidine blue; original mgn$cation, x 400.) (B) Partial4 myelinated internodes. (Teasedfiber study; original magnification. x 100.)
and thymoma {10-133. In those patients, an autoimmune cause of the neuropathy is suggested, in view of the crucial role played by the thymus in the immune surveillance. In our patients, the absence of cell infiltrates or IgG deposits would not lend support to the autoimmune hypothesis, but humoral mechanisms were not ruled out. McComas [14f reported a patient with CMFAS shortly before discovery of a malignant thymoma. The CMFAS remained for 2 years after thymectomy, and the patient developed myasthenia gravis 2 years later. He had no evidence of peripheral neuropathy. As in our patients, CMFAS appeared before diagnosis of thymoma and did not improve after tumor excision. CMFAS may be a paraneoplastic manifestation of a malignant tumor { 151. Although paraneoplastic syndromes may be relieved by tumor removal, in our patients, the lack of response to thymectomy does not necessarily rule out a paraneoplastic pathogenesis of CMFAS, and might suggest a mediation of the syndrome through memory cells.
Brief Communication: Garcia-Merino et al: Muscle Fiber Activity Syndrome 2 17
Thymoma, CMFAS, and peripheral neuropathy may be related through altered immune mechanisms, and the thymoma might be responsible for the development of CMFAS, together with or through peripheral nerve damage. We suggest that the possibility of thymoma should be considered in CMFAS, even though thymectomy does not seem to correct the syndrome.
We thank Dr C . Jimenez for sending us the second patient, Ur I. Illa for determination of anti-acetylcholine receptor antibodies, and Martha Messman for her expert technical assistance.
References 1. lsaacs H. A syndrome of continuous muscle-fibre activitv. . "1 Neurol Neurosurg Psychiatry 1961;24:319-325 2. Coers C , Telermann-Toppet N, Durdu J. Neurogenic benign fasciculations, pseudomyoronia and pseudotetany. A disease in search of a name. Arch.Neuro1 1981;38:282-287 3. Wallis WE, Poznak AV, Plum F. Generalized muscular stiffness, fasciculations, and myokymia of peripheral nerve origin. Arch Neurol 1970;22:430-439 4. Welch LK, Appenzeller 0,Ricknell JM. Peripheral neuropathy with myokymia, sustained muscular contraction, and continuous motor unit activity. Neurology 1972;22:161-168 5. Vilchez JJ, Cabello A, Benedito J, et al. Hyperkalemia paralysis, neuropathy arid persistent motor neuron discharges at rest in Addison's disease. J Neurol Neurosurg Psychiatry 1980;43: 818-822 6. Black JT, Garcia-Mullin R, Good E, et al. Muscle rigidity in a newborn due to continuous peripheral nerve hyperactivity. Arch New01 1972;27:413-42 5 7. Isaacs H , Frere G. Syndrome of continuous muscle fiber activity: histochemical, nerve terminal and end-plate study of two cases. S Afr Med J 1974;48:1601-1607 8. Lublin FD, Tsairis P, Strelecz LY, et al. Myokymia and impaired muscular relaxation with continuous motor unit activity.J Neurol Neuroscrg Psychiatry 1979;42:557-562 9. Oda K, Fukushima N, Shibasaki H, et al. Hypoxia-sensitive hyperexcitability of the intramuscular nerve axons in Isaacs' syndrome. Ann Neurol 1989;25:140-145 10. Bourouresques G, Delpuech F, Giudicelli R, et al. PolyradiculonPvrite au cours d'une myasthknie avec thymome bknin. Nouv Press Med 1981;10:25 3-2 54 11. Bogousslavsky J, Re& F, Doret AM, et al. Encephalopathy, peripheral neuropathy, dysautonomia, myasthenia gravis, malignant thymoma and antiacetylcholine receptor antibodies in the CSF. Eur Neurol 1983;22:301-306 12. Stoll DB, Lublin F, Brodovsky H, et al. Association of subacute motor neuronopathy with thymoma. Cancer 1984;54:770-772 13. Witt NJ, Bolton CF. Neuromuscular disorders and thymoma. Muscle Nerve 1988;11:398-405 14. McComas AJ. Neuromuscular function and disorders. London: Butterworths, 1977:315-317 15. Walsh JC. Neuromyotonia: an unusual presentation of intrathoracic malignancy. J Neurol Neurosurg Psychiatry 1976;39: 1086-1091
Regronal Variation in Brain Lactate in Leigh Syndrome by Localized IH Magnetic Resonance Spectroscopy John A. Detre, MD,+§ Zhiyue Wang, PhD,*P Andrew R. Bogdan, PhD,I( Debra A. Gusnard, MD," Carolyn A. Bay, MD,? Peter M. Bingham, MD,P and Robert A. Zimmerman, MD*
Localized water-suppressed 'H magnetic resonance spectroscopy was performed in an 11-month-old infant with Leigh syndrome. Spectra obtained from the basal ganglia, occipital cortex, and brainstem showed elevations in lactate, which were most pronounced in regions where abnormalities were seen with routine T2weighted magnetic resonance imaging. This approach has allowed us to examine metabolism in brain tissue directly and noninvasively, and may provide a sensitive means for evaluating metabolic disease and the response to therapy in the brain. Detre JA, Wang Z , Bogdan AR, Gusnard DA, Bay CA, Bingham PM, Zimmerman RA. Regional variation in brain lactate in Leigh syndrome by localized 'H magnetic resonance spectroscopy. Ann Neurol 1991;29:218-221
Subacute necrotizing encephalomyelopathy (Leigh syndrome) is an autosomal recessive disorder of infancy and early childhood associated with a multifactorial regional disorder of respiratory metabolism [l-51 and symmetrical spongionecrotic lesions in the basal ganglia, tectum, mesencephalopontine tegmentum, periaqueductal gray matter, and the gracilis fascicles [ 3 , 4, 61. The syndrome is clinically associated with abnormalities of muscle tone, developmental delay, seizures, emesis, intermittent tachypnea, and blindness. The diagnosis of Leigh syndrome is based largely on clinical and neuroradiological observations. Cerebrospinal fluid lactate and pyruvate levels are elevated, and blood levels are usually elevated as well. Due to the inaccessibility of brain tissue for biochemical analysis, muscle biopsy specimens E2-51, liver biopsy specimens E2, 51, and cultured fibroblasts El, 2, 4, 71, as well as other tissues, have recently been used to further characterize
From the Departments of "Radiology, +Genetics and Metabolism, and $Neurology, Children's Hospital of Philadelphia, the §Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, and IlSiemens Medical Systems, Aston, PA.
Received Jun 27, 1990. Accepted for publication Aug 15, 1990. Address correspondence to Dr Detre, Department of Neurology, Hospital of the University of Pennsylvania, 3 W Gates Building, 3400 Spruce Street, Philadelphia, PA 19104.
2 18 Copyright 0 1991 by the American Neurological Association
Continuous Muscle Fiber Activity, Peripheral Neuropathy, and Thymoma A. Garcia-Merino, MD,” A. Cabello, MD,? J. S. Mora, MD,” and H. Liatio. MU”
References 1. Jarvis GA. Huntington’s chorea in childhood. Arch Neurol 1963;9:244-257 2. Novum S, Dannd S, Goldberg MA. Intention myoclonus in Huntington’s disease. Bull LA Neurol Sci 1976;41:82-84 3. Kereshi S, Schlagenhauff RE, Richardson KS. Myoclonic and major seizures in early adult Huntington’s chorea: case-report and electroclinical findings. Clin Electroencephalogr 1980;ll: 44-47 4. Previdi P, Borgonovi R. Myoclonus and Huntington’s chorea: description of a case. Ital J Neurol Sci 1980;3:189-192 5. Berkovic SF, Andermann F, Carpenter L, Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med 1986;315:296-305 6. LeWitt PA, Truong DD, Hashimoto K, ec al. ‘Tweed Ball” mitochondropathy with a unique neurodegenerative disorder. Ann Neurol 1989;26:122 7 . Leibel RL, Shih VE, Goodman SI, et al. Glutaric acidemia: a metabolic disorder causing progressive choreoathetosis. Neurology 1980;30:1163-1168 8. Shibasaki H , Sakai T, Nishimura H, et al. Involuntary movements in chorea-acanthocytosis:a comparison with Huntington’s chorea. Ann Neurol 1982;12:311-314 9. Hallett M. Myoclonus: relation to epilepsy. Epilepsia 1985; 2 6 ( ~ ~ p1):S67-S77 pl 10. Enna SJ, Ferkany JW, Van Woert M, Butler IJ. Measurement of GABA in biological fluids: effect of GABA transaminax inhbitors. In: Chase TN, Wexler NS, Barbeau A, eds. Adv Neurol, vol 23. New York: Raven Press, 1979:741-750 11. Airaksinen EM, Leino E. Decrease of GABA in the cerebrospinal fluid of patients with progressive myoclonus epilepsy and its correlation with the decrease of 5 HIAA and HVA. Acta Neurol Scand 1982;66:666-672 12 Meldrum B, Horton R. Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA 4amino-hex-5-ynoic acid and gamma-vinyl GABA (4-amino-hex5-enoic acid). Psychopharmacology 1978;59:47-50 13 Tarsy D, Pycock CJ, Meldrum BS, Marsden CD. Focal contralateral myoclonus produced by inhibition of GABA action in the caudate nucleus of rats. Brain 1978;101:143-162 14 Van Woerr MH, Rosenbaum D, Chcng E. Biochemistry and therapeutics of posthypoxic myoclonus. In: Fahn S, Marsden CD, Van Woert MH, eds. Adv Neurol, vol 43. New York: Raven Press, 1986:171-182 15 Albin RL, Reiner A, Anderson KD, et al. Striatal and nigral subpopulations in rigid Huntington’s disease: implications for the functional anatomy of chorea and rigidity. Ann Neurol 1990;27 :357- 36 5 16 Garant DS, Gale K. Lesions of the substantid nigra protect against experimentally induced seizures. Brain Res 1783;273: 156- 161 17 Bonhaus DW, Walters JR, McNamara JO. Activation of substantia nigra neurons: role in the propagation of seizures in kindled rats. J Neurosci 1086;6:3024-3030 18 Gusella JF, Wexler NS, Connedy PM, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 1983:306:234-238
Two patients, one of them with myasthenia gravis, presented symptoms of continuous muscle fiber activity syndrome before discovery of a thymoma Peripheral neuropathy was present in both patients, with axonal and demyelinating lesions in sural nerve biopsy. T h e syndrome remained unchanged or worse after thymectomy. Both patients died of associated complications. Garcia-Merino A, Cabello A, Mora JS, Liafio H. Continuous muscle fiber activity, peripheral neuropathy, and thymoma. Ann Neurol 1991;29:215-218
The syndrome of continuous muscle fiber activity at rest (CMFAS) [ 1J associates a wide spectrum of clinical manifestations with spontaneous electromyographic (EMG) discharges. T h e condition is a polymorphous entity described under various names such as neuromyotonia, pseudomyotonia, Isms’ syndrome, and CMFAS {2). W e report here two patients with CMFAS, thymoma, and peripheral neuropathy, an association previously not recognized. T h e purpose of this report is to draw attention to the possible relevance of thymoma in the pathogenesis of the syndrome.
Patient Reports
Patient 1 A 56-year-old, previously healthy woman began to note facial twitching, blurred vision, occasional trismus, and soon after, vague thoracic discomfort. Six months after onset of symptoms, a large lymphoepithelial thymoma was found and resected. A few days after surgery, she developed profuse sweating, widespread muscle twitching, dyspnea, and carpal spasms. Serum calcium and magnesium were normal and intravenous calcium did not modify the spasms, which were only relieved by diazepam. Her condition deteriorated progressively. Her dyspnea became present on minimal effort and she developed laryngeal stridor. Extensor spasms of the
From the *Department of Neurology, Clinica Puerta de Hierro, Universidad Autdnoma de Madrid, and the TDeparment of Neuropathology, Hospital “12 de Octubre,” Madrid, Spain. Received Jul 27, 1989, and in revised form Apr 2, Jul 24, and Aug 27, 1990. Accepted for publication Aug 30, 1990. Address correspondence to Dr Garcia-Merino, Departamento de Neurologia, Clinica Puerta de Hierro, San Martin de Porres, 4, 28035 Madrid, Spain.
Copyright 0 1991 by the American Neurological Association
215
Motor Nerve Conduction Velocity Studies in the 2 Patients
Patient 1 Nerve R. median R. ulnar R. peroneal R. tibial Patient 2 Nerve R. peroneal R. tibial L. tibial
LATN (msec)
AMPL (mV)
CV ( d s e c )
F min (msec)
7.9 (2.5-4.4) 3.3 (2.1-3.3) 9.2 (3.3-6.5) 6.3 (3.0-5.8)
4.1 (5-18) 3.2 (6.6-15) 2.3 (2.5-12) 4.9 (4-19)
36 (49-70) 44 (49-70) 43 (44-57) NR (41-58)
31.7 32.3 51.5 52.1
5.0 (3.3-6.5) 7.3 (3.0-5.8) 7.5 (3.0-5.8)
2.1 (2.5-12) 5.6 (4-19) 5.2 (4-19)
41 (44-57) 35 (41-58) 38 (41-58)
52.2 (40-52) 52.5 (41-53) 51.9 (41-53)
(22-31) (22-32) (40-52) (41-53)
Normal values appear in parentheses.
LATN = distal latency; AMPL
= amplitude; CV = conduction velocity;
F rnin
=
F wave of shortest latency; R
=
right; L
=
left; NR
= no
response.
feet made walking impossible. Three months after surgery, she was bedridden and was transferred to our hospital. On admission, she had dyspnea and tachypnea at rest, hypophonia, laryngeal stridor, hyperhidrosis, and widespread myokymias. Her calf musculature was contracted and stiff, and her feet were fixed in plantar flexion. She had severe masseter contraction. An inflated cuff induced carpal spasms. Muscle strength of upper extremities and proximal muscles of lower extremities was normal. Percussion myotonia was not found, and laryngoscopy was negative. There was generalized areflexia and distal loss of vibration perception. Hemogram, blood chemistry, T, and T,, and calcium magnesium levels were normal. Antinuclear and antistriated muscle antibodies were positive at 11640 and 1/320, respectively. Motor nerve conduction studies showed moderately prolonged distal latencies and slowing of conduction to 10 to 20% below normal values (Table). Sural nerve action potentials (NAPS) were absent. Median nerve repetitive stimulation at 3 Hz was normal. Concentric needle exam of first dorsal interosseus, tibialis anterior, and medial gastrocnemius revealed continuous muscle fiber activity at rest, which was composed of bursts of normal and polyphasic units firing at variable frequencies, neuromyotonic discharges, and occasional triplets and multiplets. Fibrillation potentials, positive sharp waves, fasciculations, or myotonic discharges were not recorded. Inflation of a proximal blood cuff produced immediate cessation of activity, which returned 30 seconds later at a lesser intensity on maintenance of ischemia. Sciatic nerve block at the popliteal fossa reduced moderately the frequency of discharges. ELECTROPHYSIOLOGICALSTUDIES.
PATHOLOGICAL STUDIES. Small atrophic angulated muscle fibers were present on gastrocnemius muscle biopsy, together with type grouping (Fig 1). On surd nerve biopsy, there was a mild to moderate loss of large myelinated fibers (5,890/mmZ),frequent vacuolization and splitting of the myelin sheath's outer lamellae, and paranodal demyelination by electron microscopy (not shown).
Three days after admission, the patient suffered a respiratory arrest during a prolonged episode of
CLINICAL COURSE.
216 Annals of Neurology Vol 29 N o 2 February 1991
Fig I . Patient 1. Skeletal muscle. Atrophic, angulatedlfibersare seen in one fascicle, together with type I grouping. (Adenosine tripbospbatase pH 9.4; original magnijkation,, x 1OO.j
laryngeal stridor. She was intubated and placed on a respirator. One day later, she developed severe abdominal pain and shock. An emergency laparotomy revealed a massive mesenteric thrombosis, and the patient died a few hours later. Autopsy was not authorized.
Patient 2 A 68-year-old man with chronic bronchitis had a 12-year history of myasthenia gravis, which was adequately controlled by low doses of pyridostigmine bromide. Two months before admission, he developed nasal voice, dysphagia, regurgitation, and generalized weakness, accompanied by mild dyspnea, profuse perspiration, somnolence, and lower extremity myokymias. A mediastinal mass was found on radiography, and he was referred to our hospital for surgery. O n admission, besides prior symptoms, he had early fatigue on resistive testing of proximal muscles but no ptosis or diplopia. H e was areflexic and had loss of vibration perception in lower limbs. An edrophonium test relieved moderately his nasal speech and early fatigability. Blood chemistry was normal. Antinuclear and antistriated muscle antibodies were positive
at l/l60 and 11320, respectively. Acetylcholine receptor antibodies were 6 nmol/L. ELECTROPHYSIOLOGICM- STUDIES. He had moderately prolonged motor distal latencies, mild slowing of motor conduction to 10 to 20% below normal values, and absent sural NAPS.Facial nerve repetitive stimulation at 1 Hz produced a 21% decrement of the fifth potential. Needle exam of the left tibialis anterior and medial gastrocnemius muscles revealed spontaneous activity composed of bursts of normal units firing at variable rates, sometimes as high as 40 Hz, neuromyotonic discharges, and electrical myokymia. Sciatic nerve block at the popliteal fossa reduced the activity moderately. PATHOLOGICAL STUDIES. Lateral gastrocnemius muscle biopsy with oxidative enzyme staining showed abundant small, dark, angulated fibers and type grouping. Surd nerve biopsy revealed mild to moderate loss of large myelinated fibers (6,7041mm2) and some vacuolation of myelin sheaths (Fig 2A). On electron microscopy, there was extensive vacuolation and dehiscence of the myelin outer lamellae, and in some axons, high concentration of granular material. Teased fibers showed instances of segmental demyelination and remyelination (Fig 2B). Staining with antihuman IgG peroxidase antibodies did not disclose IgG deposits in nerve.
A large epithelial thymic tumor infiltrating pleura and pericardium was removed at thoracotomy. Bronchopulmonary infections complicated the postoperative course, and the man was never able to breathe without assisted respiration. His muscle twitching did not respond well to 800 mgiday of carbamazepine but worsened with anticholinesterase therapy, as did the sweating. The patient’s circulatory instability impeded adequate plasma exchanges. Steroid therapy from an initial dose of 2 mg/kg/day of rnethylprednisolone to a final dose of 20 mg daily, in 6 weeks, did not produce a significant improvement. The patient died 45 days after surgery. Autopsy was not performed. CLINICAL COURSE.
Discassion It has been suggested that the muscle hyperactivity of CMFAS is due to partial loss of motor innervation, compensated by collateral sprouting of survival axons {2]. CMFAS has been associated with different peripheral neuropathies, but the pathological information is very limited. Axonal damage 131, segmental demyelination [4, 53, or both [b] have been reported. In many patients, the surd nerve was normal or showed minimal changes. In others, an increased collateral ramification of terminal motor axons at the preterminal level has been detected [2, 7, 81, expressing denervation without disease specificity. Recently, extensive terminal arborizations in the endplates have been described 191. In our patients, damage to the myelin sheaths seemed independent of the axonal lesion, but the electrophysiologiral results suggested an axonal type of neuropathy . There are a few reports of peripheral nerve disease
Fig 2. Patient 2. Surval nerve. (A) Loss of myelinatedfibers and Some completely demyelinated axons. (Semithin section, toluidine blue; original mgn$cation, x 400.) (B) Partial4 myelinated internodes. (Teasedfiber study; original magnification. x 100.)
and thymoma {10-133. In those patients, an autoimmune cause of the neuropathy is suggested, in view of the crucial role played by the thymus in the immune surveillance. In our patients, the absence of cell infiltrates or IgG deposits would not lend support to the autoimmune hypothesis, but humoral mechanisms were not ruled out. McComas [14f reported a patient with CMFAS shortly before discovery of a malignant thymoma. The CMFAS remained for 2 years after thymectomy, and the patient developed myasthenia gravis 2 years later. He had no evidence of peripheral neuropathy. As in our patients, CMFAS appeared before diagnosis of thymoma and did not improve after tumor excision. CMFAS may be a paraneoplastic manifestation of a malignant tumor { 151. Although paraneoplastic syndromes may be relieved by tumor removal, in our patients, the lack of response to thymectomy does not necessarily rule out a paraneoplastic pathogenesis of CMFAS, and might suggest a mediation of the syndrome through memory cells.
Brief Communication: Garcia-Merino et al: Muscle Fiber Activity Syndrome 2 17
Thymoma, CMFAS, and peripheral neuropathy may be related through altered immune mechanisms, and the thymoma might be responsible for the development of CMFAS, together with or through peripheral nerve damage. We suggest that the possibility of thymoma should be considered in CMFAS, even though thymectomy does not seem to correct the syndrome.
We thank Dr C . Jimenez for sending us the second patient, Ur I. Illa for determination of anti-acetylcholine receptor antibodies, and Martha Messman for her expert technical assistance.
References 1. lsaacs H. A syndrome of continuous muscle-fibre activitv. . "1 Neurol Neurosurg Psychiatry 1961;24:319-325 2. Coers C , Telermann-Toppet N, Durdu J. Neurogenic benign fasciculations, pseudomyoronia and pseudotetany. A disease in search of a name. Arch.Neuro1 1981;38:282-287 3. Wallis WE, Poznak AV, Plum F. Generalized muscular stiffness, fasciculations, and myokymia of peripheral nerve origin. Arch Neurol 1970;22:430-439 4. Welch LK, Appenzeller 0,Ricknell JM. Peripheral neuropathy with myokymia, sustained muscular contraction, and continuous motor unit activity. Neurology 1972;22:161-168 5. Vilchez JJ, Cabello A, Benedito J, et al. Hyperkalemia paralysis, neuropathy arid persistent motor neuron discharges at rest in Addison's disease. J Neurol Neurosurg Psychiatry 1980;43: 818-822 6. Black JT, Garcia-Mullin R, Good E, et al. Muscle rigidity in a newborn due to continuous peripheral nerve hyperactivity. Arch New01 1972;27:413-42 5 7. Isaacs H , Frere G. Syndrome of continuous muscle fiber activity: histochemical, nerve terminal and end-plate study of two cases. S Afr Med J 1974;48:1601-1607 8. Lublin FD, Tsairis P, Strelecz LY, et al. Myokymia and impaired muscular relaxation with continuous motor unit activity.J Neurol Neuroscrg Psychiatry 1979;42:557-562 9. Oda K, Fukushima N, Shibasaki H, et al. Hypoxia-sensitive hyperexcitability of the intramuscular nerve axons in Isaacs' syndrome. Ann Neurol 1989;25:140-145 10. Bourouresques G, Delpuech F, Giudicelli R, et al. PolyradiculonPvrite au cours d'une myasthknie avec thymome bknin. Nouv Press Med 1981;10:25 3-2 54 11. Bogousslavsky J, Re& F, Doret AM, et al. Encephalopathy, peripheral neuropathy, dysautonomia, myasthenia gravis, malignant thymoma and antiacetylcholine receptor antibodies in the CSF. Eur Neurol 1983;22:301-306 12. Stoll DB, Lublin F, Brodovsky H, et al. Association of subacute motor neuronopathy with thymoma. Cancer 1984;54:770-772 13. Witt NJ, Bolton CF. Neuromuscular disorders and thymoma. Muscle Nerve 1988;11:398-405 14. McComas AJ. Neuromuscular function and disorders. London: Butterworths, 1977:315-317 15. Walsh JC. Neuromyotonia: an unusual presentation of intrathoracic malignancy. J Neurol Neurosurg Psychiatry 1976;39: 1086-1091
Regronal Variation in Brain Lactate in Leigh Syndrome by Localized IH Magnetic Resonance Spectroscopy John A. Detre, MD,+§ Zhiyue Wang, PhD,*P Andrew R. Bogdan, PhD,I( Debra A. Gusnard, MD," Carolyn A. Bay, MD,? Peter M. Bingham, MD,P and Robert A. Zimmerman, MD*
Localized water-suppressed 'H magnetic resonance spectroscopy was performed in an 11-month-old infant with Leigh syndrome. Spectra obtained from the basal ganglia, occipital cortex, and brainstem showed elevations in lactate, which were most pronounced in regions where abnormalities were seen with routine T2weighted magnetic resonance imaging. This approach has allowed us to examine metabolism in brain tissue directly and noninvasively, and may provide a sensitive means for evaluating metabolic disease and the response to therapy in the brain. Detre JA, Wang Z , Bogdan AR, Gusnard DA, Bay CA, Bingham PM, Zimmerman RA. Regional variation in brain lactate in Leigh syndrome by localized 'H magnetic resonance spectroscopy. Ann Neurol 1991;29:218-221
Subacute necrotizing encephalomyelopathy (Leigh syndrome) is an autosomal recessive disorder of infancy and early childhood associated with a multifactorial regional disorder of respiratory metabolism [l-51 and symmetrical spongionecrotic lesions in the basal ganglia, tectum, mesencephalopontine tegmentum, periaqueductal gray matter, and the gracilis fascicles [ 3 , 4, 61. The syndrome is clinically associated with abnormalities of muscle tone, developmental delay, seizures, emesis, intermittent tachypnea, and blindness. The diagnosis of Leigh syndrome is based largely on clinical and neuroradiological observations. Cerebrospinal fluid lactate and pyruvate levels are elevated, and blood levels are usually elevated as well. Due to the inaccessibility of brain tissue for biochemical analysis, muscle biopsy specimens E2-51, liver biopsy specimens E2, 51, and cultured fibroblasts El, 2, 4, 71, as well as other tissues, have recently been used to further characterize
From the Departments of "Radiology, +Genetics and Metabolism, and $Neurology, Children's Hospital of Philadelphia, the §Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, and IlSiemens Medical Systems, Aston, PA.
Received Jun 27, 1990. Accepted for publication Aug 15, 1990. Address correspondence to Dr Detre, Department of Neurology, Hospital of the University of Pennsylvania, 3 W Gates Building, 3400 Spruce Street, Philadelphia, PA 19104.
2 18 Copyright 0 1991 by the American Neurological Association
